Paclitaxel activity for the treatment of non-Hodgkin's lymphoma: final report of a phase II trial

In order to determine the activity of paclitaxel in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), we conducted a phase II clinical trial in which eligible patients received paclitaxel 200 mg/m² intravenously over 3 h. Treatment was repeated every 3 weeks. Patients achieving complete or partial responses after two courses of paclitaxel continued to receive therapy for a maximum of eight courses, otherwise they were removed from the study. Of 96 evaluable patients, 45 (47%) had primary refractory disease, and 51 (53%) had relapsed lymphoma. The median number of prior treatment regimens was two (range one to 10 regimens). 45 patients had low-grade, 44 had intermediate-grade, and seven had mantle cell lymphoma. 24/96 patients responded (10 complete and 14 partial remissions) for an overall response rate of 25% (95% CI 17–35%). Patients with relapsed lymphoma had a higher response rate than those with primary refractory disease (19/51=37% v 5/45 =11%; P  < 0.01), and patients with relapsed intermediate-grade lymphoma had a higher response than those with relapsed low-grade lymphoma (9/18=50% v 10/31 = 32%; P  = 0.22). The treatment was very well tolerated with the most common side-effects being alopecia (100%), peripheral neuropathy (35% of ≥ grade II), and arthralgia/myalgia (25% of ≥ grade II). After the first course of paclitaxel, grade III/IV thrombocytopenia and neutropenia were observed in 21% and 23% of the patients respectively. 23 episodes of neutropenic fever developed after 250 courses of paclitaxel therapy (8%). We conclude that paclitaxel, at this dose and schedule, is an active new drug for the treatment of non-Hodgkin's lymphoma. The activity of paclitaxel combination programmes are currently under investigation.     

Interferon-γ signal transduction during parasite infection: modulation of MAP kinases in the infection of human monocyte cells (THP1) by Toxoplasma gondii

We assayed mitogen-activated protein (MAP) kinase phosphorylation in a human monocyte cell line (THP1) during their infection by Toxoplasma gondii . In addition, we tested the effect of specific MAP kinase inhibitors (PD098059 and SB203580) on parasite invasion. MAP kinase phosphorylation was increased in the cytosol and membrane fractions of THP1 infected with T. gondii . The MAP kinase phosphorylation of uninfected THP1 cells was not significantly modified by incubation for 20 h with 1000 U/ml of IFN-γ. However, IFN-γ treatment of infected cells significantly reduces the increase in phosphorylation caused by parasite infection. There was also MAP kinase activity in the cytosol and membrane fractions of extracellular T. gondii tachyzoites. IFN-γ altered the distribution of activity in subcellular fractions of extracellular T. gondii tachyzoites. This indicates that IFN-γ directly affects parasite MAP kinase activity. The results provide evidence that MAP kinase pathways participate in the infection by T. gondii and that the decrease in MAP kinase activity in infected cells caused by IFN-γ may be involved in mediating their protective signals .     

Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1

Aim Difficulties in neurocognition and social interaction are the most prominent causes of morbidity and long‐term disability in children with neurofibromatosis type 1 (NF1). Symptoms of attention‐deficit–hyperactivity disorder (ADHD) have also been extensively recognized in NF1. However, systematic evaluation of symptoms of autism spectrum disorder (ASD) in children with NF1 has been limited. Method We present a retrospective, cross‐sectional study of the prevalence of symptoms of ASD and ADHD and their relationship in a consecutive series of 66 patients from our NF1 clinic. The Social Responsiveness Scale and the Vanderbilt ADHD Diagnostic Parent Rating Scale were used to assess symptoms of ASD and ADHD. Results Sixty‐six participants (42 males, 24 females) were included in this study. Mean age at assessment was 10 years 11 months (SD 5y 4mo). Forty percent of our NF1 sample had raised symptom levels reaching clinical significance on the Social Responsiveness Scale (T ≥ 60), and 14% reached levels consistent with those seen in children with ASDs (T ≥ 75). These raised levels were not explained by NF1 disease severity or externalizing/internalizing behavioral disorders. There was a statistically significant relationship between symptoms of ADHD and ASD (χ²=9.11, df=1, p=0.003, φ=0.56). Particularly salient were the relationships between attention and hyperactivity deficits, with impairments in social awareness and social motivation. Interpretation We found that symptoms of ASD in our NF1 population were raised, consistent with previous reports. Further characterization of the specific ASD symptoms and their impact on daily function is fundamental to the development and implementation of effective interventions in this population, which will probably include a combination of medical and behavioral approaches.     

Intracoronary Radiation Post PTCA Prevents Late Arterial Constriction

Vascular constriction post PTCA is a major component in the mechanism of restenosis following intervention. Ionizing radiation demonstrated reduction of neointima formation after injury in animal models and lowered the restenosis rates in pilot clinical studies. To determine the effect of intracoronary radiation therapy on vascular remodeling, angiograms from two radiation trials were analyzed by QCA methods. Patients in these trials had de novo lesions and were treated with balloon angioplasty followed by either beta or gamma radiation. All patients were studied angiographically at 6 months; patients with total occlusion at the treated artery were excluded from the analysis. In the gamma trial, 192-Iridium was utilized in 14 patients (15 lesions) with doses between 20-25 Gy. In the beta trial, 90-Sr/Y was utilized in 17 patients (17 lesions) with doses between 12-16 Gy. The QCA analysis from these studies demonstrated negative late loss and late loss index at six months for patients from the beta (-0.02 ± 0.3) and the gamma (-0.19 ± 0. 3) study. The effect of positive remodeling was maintained at 24 months, -0.16 ± 0.4 in the gamma group. Larger MLD at follow-up compared to the immediate post MLD were demonstrated in 50% of the patients from both studies. Thus, intracoronary radiation resulted in lower late loss and late loss index rates than previously reported following balloon angioplasty alone suggesting a positive vascular remodeling effect of intracoronary radiation.     

MALIGNANT MELANOMA IN CHILDREN

Background. While significant risk factors for malignant melanoma may initially develop or are first seen in childhood, the actual occurrence of this neoplasm in prepubertal children is uncommon. Methods. A retrospective study of malignant melanoma in Puerto Ricans up to 16 years of age occurring from 1973 to 1990 was carried out by identifying those cases in the Puerto Rico Cancer Registry. Results. A total of seven cases were found consisting of three boys and four girls with ages ranging from 22 months to 16 years and comprising 0.94% of the total melanomas. In three of the seven cases, there was a history of a previously existent small congenital melanocytic nevus on the area. Three cases were Clark's level I, two level II, and in two cases with proved metastatic disease, Clark's level of invasion were not reported. Those cases with Clark's level I and II had a 100% 5-year survival. Conclusions. Although rare, malignant melanoma in children can be as aggressive as in adults. Among the known factors predisposing to malignant melanoma, three out of seven cases developed within a small congenital nevus, two of which occurred during the first decade of life. Due to the rarity of this event in our population, it appears unreasonable to excise all small congenital nevi during the first decade of life. Even for those who advocate excision of all small congenital nevi, the evidence at present suggests that such small nevi very rarely undergo malignant change before puberty and therefore a policy of observation in childhood and offering excision around the time of puberty is perfectly logical.     

BIOLOGICAL SIMILARITIES AND DIFFERENCES BETWEEN RATS GENETICALLY DIFFERENT IN ALCOHOL PREFERENCE

This paper is an inventory of some behavioural, biochemicaland pharmacological similarities and differences between twoinbred strains of Wistar rats differing in voluntary consumptionof ethanol, namely: UChA and UChB with low and high preferencesrespectively for ethanol under conditions involving free choicebetween a 10% (v/v) ethanol solution and distilled water. Thefollowing strain differences were observed: ethanol consumption(UChA<UChB); total water consumption (UChA<UChB); solidfood consumption (UChA>UChB); rate of recovery of ethanollabel in expired CO₂ (UChA<UChB); oxidation of ethanol toacetaldehyde by brain homogenates (UChA>UChB); acetaldehydedisposal by brain homogenates (UChA<UChB); ethanol (90 mmol/kg,i.p.) sleeping-time (UChA<UChB); chronic and acute toleranceto ethanol (UChA developed it, whereas UChB did not); lethaldoses of ethanol (UChA>UChB); recovery rate of the labelof gluconate in expired CO₂ (UChA<UChB); recovery rate ofthe label of fructose in expired CO₂ (UChA<UChB); blood-glucoselevel after glucose (1g/kg, i.p.) load (UChA<UChB). No straindifferences were observed in the rate of recovery in expiredCO₂ of the label of the following substrates: acetate, pyruvate,butyrate, citrate, ribose, glycerol, sorbitol, glucose and galactose.